Colon cancer is the third most common cancer in both men and women, and is the second leading cause of cancer death in the United States. There is a need for new approaches to prevent and treat this disease as the current strategies of chemotherapy and surgical treatments are not effective for late stage colon cancer. Inflammation is a major risk factor for colon cancer, and identifying pathways involved in both inflammation and cancer will provide new therapeutic targets for the treatment of colon cancer. Hypoxia-inducible factors (HIFs) are heterodimeric transcription factors consisting of an alpha subunit (HIF1a or HIF2a) and beta subunit (aryl hydrocarbon nuclear translocator (ARNT)). HIF2a is expressed in colon epithelial cells, although little is known about HIF2a function in these cells. Our recent data demonstrates that the activation of HIF2a potentiates intestinal inflammation and colon cancer. The long-term objectives of the proposed studies are to elucidate how HIF2a impact these processes as an impetus to the development of therapeutic regimens that can be used to treat colon cancer. The specific hypothesis of this proposal is that chronic activation of HIF2 a signaling induces proinflammatory mediators leading to an increase in colon carcinogenesis. This hypothesis is based on our recent data demonstrating: 1) Intestine-specific activation of HIF2a leads to chronic colon inflammation. 2) Disruption of HIF2a in the colon protects from acute intestinal inflammation. 3) The proinflammatory mediators, macrophage migration inhibitory factor (MIF) and prostaglandin E2 (PGE2) are early initiating factors in HIF2a-induced colon inflammation. 4) HIF2a increases colon cancer cell growth and carcinogenesis. Based on these observations, the experimental focus of this proposal is on the regulatory role of HIF2a in the pathogenesis of colon inflammation and cancer through the following 3 interconnected specific aims:
Aim 1 : determine the role of MIF and cyclooxygenase-2 (COX2)-derived PGE2 in HIF2a- promoted colon cancer cell growth. This will be examined in the intestine-specific HIF2a overexpressing mice and in colon-derived cell lines that overexpress HIF2a.
Aim 2 : determine the requirement for HIF2a in colitis- associated colon carcinogenesis (CAC). This will be examined in a well-characterized CAC model using azoxymethane (AOM) and dextran sulfate sodium (DSS) in mice that are disrupted for HIF2a or mice that overexpress HIF2a specifically in the colon.
Aim 3 : assess the molecular basis by which HIF2a regulates the expression of proinflammatory mediators. This will be examined by promoter and gene expression analysis with a focus on HIF2a target genes relevant to the development of colon inflammation.
This Aim will also identify novel proinflammatory targets of HIF2a using genome-wide gene expression analysis and promoter binding studies in colon tissues isolated from Aim 2. Taken together, the proposed in vivo and in vitro studies will provide novel insights into the fundamental aspects of HIF2a function in the colon. Ultimately these studies will determine if HIF2a is a potential therapeutic target in colon inflammation and may provide an alternative strategy for preventing and treating colon cancer.

Public Health Relevance

Colon cancer is the third most common cancer in both men and women, and is the second leading cause of cancer death in the United States. Inflammation is a major risk factor for colon cancer. This proposal examines the role of HIF in the regulation of inflammation and colon cancer. The goal of this work is to determine if HIF represents a new target for the prevention and treatment of colon cancer. The proposal has relevance for patients with ulcerative colitis, Crohn's disease and colon cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Clinical, Integrative and Molecular Gastroenterology Study Section (CIMG)
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Umar, Asad
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University of Michigan Ann Arbor
Schools of Medicine
Ann Arbor
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Dame, Michael K; Attili, Durga; McClintock, Shannon D et al. (2018) Identification, isolation and characterization of human LGR5-positive colon adenoma cells. Development 145:
Sherman, Matthew A; Suresh, Madathilparambil V; Dolgachev, Vladislav A et al. (2018) Molecular Characterization of Hypoxic Alveolar Epithelial Cells After Lung Contusion Indicates an Important Role for HIF-1?. Ann Surg 267:382-391
Ji, Tuo; Takabayashi, Hidehiko; Mao, Maria et al. (2017) Regulation and function of bone morphogenetic protein signaling in colonic injury and inflammation. Am J Physiol Gastrointest Liver Physiol 312:G24-G33
Xue, Xiang; Bredell, Bryce X; Anderson, Erik R et al. (2017) Quantitative proteomics identifies STEAP4 as a critical regulator of mitochondrial dysfunction linking inflammation and colon cancer. Proc Natl Acad Sci U S A 114:E9608-E9617
Ma, Xiaoya; Zhang, Huabing; Xue, Xiang et al. (2017) Hypoxia-inducible factor 2? (HIF-2?) promotes colon cancer growth by potentiating Yes-associated protein 1 (YAP1) activity. J Biol Chem 292:17046-17056
Ma, Xiaoya; Pham, Vinh T; Mori, Hiroyuki et al. (2017) Iron elevation and adipose tissue remodeling in the epididymal depot of a mouse model of polygenic obesity. PLoS One 12:e0179889
Triner, Daniel; Xue, Xiang; Schwartz, Andrew J et al. (2017) Epithelial Hypoxia-Inducible Factor 2? Facilitates the Progression of Colon Tumors through Recruiting Neutrophils. Mol Cell Biol 37:
Shah, Yatrik M (2016) The role of hypoxia in intestinal inflammation. Mol Cell Pediatr 3:1
Essien, Bryan E; Sundaresan, Sinju; Ocadiz-Ruiz, Ramon et al. (2016) Transcription Factor ZBP-89 Drives a Feedforward Loop of ?-Catenin Expression in Colorectal Cancer. Cancer Res 76:6877-6887
Ramakrishnan, Sadeesh K; Shah, Yatrik M (2016) Role of Intestinal HIF-2? in Health and Disease. Annu Rev Physiol 78:301-25

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